Compositions and methods for inhibiting H2 histamine receptors

ABSTRACT

Heterocyclic compounds which are inhibitors of histamine activity, in particular, inhibitors of H-2 histamine receptors. A specific compound of this invention is 2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone.

This is a division of application Ser. No. 463,647 filed Apr. 24, 1974,now U.S. Pat. No. 3,932,644.

This invention relates to pharmacologically active compounds andpharmaceutical compositions and methods of inhibiting H-2 histaminereceptors with these compounds. The compounds of the invention can existas the addition salts but, for convenience, reference will be madethroughout this specification to the parent compounds.

It has long been postulated that many of the physiologically activesubstances within the animal body, in the course of their activity,combine with certain specific sites known as receptors. Histamine is acompound which is believed to act in such a way but, since the actionsof histamine fall into more than one type, it is believed that there ismore than one type of histamine receptor. The type of action ofhistamine which is blocked by drugs commonly called "antihistamines" (ofwhich mepyramine is a typical example) is believed to involve a receptorwhich has been designated as H-1. A further group of substances hasrecently been described by Black et. al. (Nature 1972, 236, 385) whichare distinguished by the fact that they act at histamine receptors otherthan the H-1 receptor and these other receptors have been designated asH-2 receptors. This latter group of substances, to certain of which thepresent invention relates, are thus of utility in inhibiting certainactions of histamine which are not inhibited by the above mentionedantihistamines. The substances of this invention may also be of utilityas inhibitors of certain actions of gastrin.

Black et al., cited above, page 390, column 2, state the following:"Mepyramine has been defined as an H₁ -receptor antagonist¹ andburimamide has now been defined as an H₂ -receptor antagonist. Usedalone, burimamide can antagonize those responses to histamine, such asstimulation of acid gastric secretion, which cannot be blocked bymepyramine; histamine apparently activates H₂ -receptors to producethese effects." Thus, from the Black et al. paper, H-2 histaminereceptors are those histamine receptors which are not inhibited bymepyramine but are inhibited by burimamide.

Throughout the present specification, by the term "lower alkyl" we meanan alkyl group containing from 1 to 4 carbon atoms.

The compounds with which the present invention is concerned may berepresented by the following general formula; ##STR1## wherein A takentogether with the nitrogen and carbon atoms shown forms a pyrimidine,imidazoline, quinazoline, pyridine, benzothiadiazine, 1,2,4-thiadiazine,thiazoline, 1,2,4-triazine or quinoline ring, said ring having a keto,thione or sulfone group and optionally substituted by one or two lowealkyl, phenyl or benzyl groups; R is a grouping of the structute shownin Formula II;

    het--CH.sub.2 Z(CH.sub.2).sub.n --                         FORMULA II

wherein Het is a nitrogen containing heterocyclic ring such asimidazole, pyridine, thiazole, isothiazole or thiadiazole which ring isoptionally substituted by lower alkyl preferably methyl, amino, hydroxyor halogen; Z is sulphur or a methylene group; and n is 2 or 3, or apharmaceutically acceptable acid addition salt thereof.

It will be understood that, since the ring structures formed arepotentially tautomeric systems, the Formula I shown is only one ofseveral possible representations.

Particularly important classes of compounds which fall within the scopeof Formula I are the compounds of the following Formulae III to VI:##STR2## Wherein R has the same significance as in Formula I, X isoxygen or sulphur; Y₁ and Y₂, which may be the same or different, arehydrogen, lower alkyl, phenyl or benzyl or Y₁ and Y₂ together with theadjacent carbon atoms may form a phenyl ring; and Y₃ and Y₄ which may bethe same or different, are hydrogen, lower alkyl, phenyl or benzyl.

Particularly useful compounds of formulae I and III to VI are thosewherein Het is imidazole, optionally substituted by methyl. It is alsopreferred that n should be 2.

Specific compounds of this invention having advantageous utility are:

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone,

2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one and

3-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide.

The compounds of the present invention may be produced by the reactionof a compound of Formula VII or of Formula VIII: ##STR3## wherein A hasthe same significance as in Formula I, B is a chain of three or fouratoms which are either all carbon atoms or which comprise a sulphurand/or one or two nitrogen atoms which chain also comprises a protectedketo or thione grouping, and Q is a reactive grouping such as halogen,methanesulphonyl, thiol or alkylthio such as methylthio with an aminocompound of formula R¹ NH₂ wherein R¹ may have the same significance asR in Formula I or may be a group such that the product from its reactionwith the compound of Formula VI or VIII may be converted by one or morereactions to a compound of Formula I.

As stated above, the compounds represented by Formula I have been foundto have pharmacological activity in the animal body as antogonists tocertain actions of histamine which are not blocked by antihistaminessuch as mepyramine. For example, they have been found to inhibitselectively the histamine-stimulated secretion of gastric acid from theperfused stomachs of rats anaestherised with urethane at doses of from 2to 256 micromoles per kilogram intravenously. Similarly, the action ofthese compounds may be demonstrated by their antagonism to the effectsof histamine on other tissues which, according to the above-mentionedpaper of Black et. al., are H-2 receptors. Examples of such tissues areperfused isolated guinea-pig heart, isolated guinea-pig right atrium andisolated rat uterus. The compounds of the invention have also been foundto inhibit the secretion of gastric acid stimulated by pentagastrin orby food.

The level of activity found for the compounds of the present inventionis illustrated by the effective dose range in the anaesthetised rat, asmentioned above of from 2 to 256 micromoles per kilogram, givenintravenously. Many of the compounds of the present invention produce a50% inhibition in this test at a dose of from 5 to 20 micromoles perkilogram.

For therapeutic use, the phamacologically active compounds of thepresent invention will normally be administered as a pharmaceuticalcomposition comprising as the or an essential active ingredient at leastone such compound in the basic form or in the form of an addition saltwith a pharmaceutically acceptable acid and in association with aphamaceutical carrier therefor.

Such addition salts include those with hydrochloric, hydrobromic,hydriodic, sulphuric and maleic acids and may conveniently be formedfrom the corresponding base by treatment of the latter with a dilutesolution of the appropriate acid followed by recrystallisation from asuitable solvent such as aqueous ethanol.

Pharmaceutical compositions comprising a pharmaceutical carrier and acompound of formula I or a pharmaceutically acceptable acid additionsalt thereof and methods of inhibiting H-2 histamine receptors whichcomprise administering a compound of formula I or a pharmaceuticallyacceptable acid addition salt thereof are also objects of thisinvention.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used, the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form, or in the form of a troche orlozenge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg to about 1 gm. If a liquid carrier is used, thepreparation may be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampoule, or an aqueous ornonaqueous liquid suspension.

The pharmaceutical compositions are prepared by conventional techniquesinvolving procedures such as mixing, granulating and compressing ordissolving the ingredients as appropriate to the desired preparation.

The active ingredient will be present in the composition in an effectiveamount to inhibit histamine activity. The route of administration may beorally or parenterally.

Preferably, each dosage unit will contain the active ingredient in anamount of from about 50 mg to about 250 mg most preferably from about100 mg to about 200 mg.

The active ingredient will preferably be administered in equal doses oneto three times per day. The daily dosage regimen will preferably be fromabout 150 mg to about 750 mg most preferably from about 300 mg to about600 mg.

Other pharmacologically active compounds may in certain cases beincluded in the composition. Advantageously the composition will be madeup in a dosage unit form appropriate to the desired mode ofadministration, for example as a tablet, capsule or injectable solution.

The invention is illustrated but in no way limited by the followingexamples:

EXAMPLE 1 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidonedihydrochloride

An intimate mixture of4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.6 g) and2-methylthio-4-pyrimidone (1.4 g) was heated to 150° over a period of 30minutes, and then at 150°-160° for 2 hours. After cooling, the reactionmixture was triturated under water to give the crude base, which wasfiltered off and dissolved in 5N hydrochloric acid. Evaporation todryness followed by recrystallisation of the residue from aqueousethanol gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidonedihydrochloride (2.1 g), m.p. 246°-248°.

(Found: C, 39.25; H, 5.2; N, 20.4; S, 9.6; Cl, 20.5; C₁₁ H₁₇ Cl₂ N₅ OS.requires: C, 39.1; H, 5.1; N, 20.7; S, 9.5; Cl, 20.95).

Recrystallisation of the initial crude base from ethanol/water gave thepure base, m.p. 219°-221°.

EXAMPLE 22-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-[(2-aminoethyl)thiomethyl]-5(4)-methylimidazole (4.5g.) with 6-methyl-2-methylthio-4-pyrimidone (2.7 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-4-pyrimidonedihydrochloride, m.p. 247°-250° (ex ethanol).

(Found: C, 41.1; H, 5.7; N, 19.8; S, 8.9; Cl, 19.8; C₁₂ H₁₉ Cl₂ N₅ OS.requires: C, 40.9; H, 5.4; N, 19.9; S, 9.1; Cl, 20.1).

EXAMPLE 32-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5,6-dimethyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (4.1 g.)with 5,6-dimethyl-2-methylthio-4-pyrimidone (2.6 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5,6-dimethyl-4-pyrimidonedihydrochloride, m.p. 235°-237° (ex methanol).

(Found: C, 42.8; H, 6.0; N, 18.7; S, 8.6; Cl, 18.8; C₁₃ H₂₁ Cl₂ N₅ OS.requires: C, 42.6; H, 5.8; N, 19.1; S, 8.75; Cl, 19.4).

EXAMPLE 4 2-[4-(4-Imidazolyl)butylamino]-4-pyrimidone dihydrochloride

Reaction of 4(5)-(4-aminobutyl)imidazole (2.1 g.) with2-methylthio-4-pyrimidone (1.4 g.) by the method described in Example 1gave 2-[4-(4-imidazolyl)butylamino]-4-pyrimidone dihydrochloride, m.p.215°-222° (ex ethanol).

(Found: C, 43.15; H, 5.6; N, 22.5; Cl, 22.8; C₁₁ H₁₇ Cl₂ N₅ O requires:C, 43.15; H, 5.6; N, 22.9; Cl, 23.2).

EXAMPLE 54-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-thiopyrimidonedihydrochloride

A solution of 4(5)-[(2-aminoethyl)thiomethyl]-5(4)-methylimidazole (7.4g.) and 2,4-dimercaptopyrimidine (4.1 g.) in water (150 ml.) was heatedunder reflux for 12 hours. After cooling the precipitated oil wasseparated by decantation, washed with water (3 × 50 ml.), and dissolvedin 2N hydrochloric acid. The solution was evaporated to dryness and theresidue recrystallised from ethanol to give4-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-thiopyrimidonedihydrochloride, m.p. 254°-257°.

(Found: C, 37.2; H, 4.9; N, 19.7; S, 18.0; C₁₁ H₁₇ Cl₂ N₅ S₂. requires:C, 37.3; H, 4.8; N, 19.8; S, 18.1).

EXAMPLE 6 4-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-pyrimidone

A solution of4-[2-(4-methyl-5-imidazolylmethythio)ethylamino]-2-thiopyrimidonedihydrochloride (1.0 g.) and chloracetic acid (0.35 g.) in water (5 ml.)was heated on a steam bath for 40 min. Concentrated hydrochloric acid (8ml.) was then added, the solution heated under reflux for 2 hours, andthen evaporated to dryness. The residual oil was dissolved in water (5ml.) basified with ammonium hydroxide and the precipitate washed withhot water to give4-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-pyrimidone, m.p.249°-251°.

(Found: C, 49.5; H, 5.6; N, 26.3; S, 18.0; C₁₁ H₁₅ N₅ OS. requires: C,49.8; H, 5.7; N, 26.4; S, 18.1).

EXAMPLE 72-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-2-imidazoline-4-onedihydrochloride

A solution of 4(5)-(2-aminoethyl)thiomethyl-5-(4)-methylimidazole (3.4g.) and 2-methylthio-2-imidazolin-4-one hydroidide (2.6 g.) in dryethanol (20 ml.) was left to stand at room temperature for 4 days. Thecrude product was filtered off, dissolved in dilute hydrochloric acidand the solution basified with aqueous potassium carbonate solution togive2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one,m.p. 224°-5° (decomp.). The dihydrochloride, m.p. 226°-228° (decomp.)was obtained by dissolving the base in dilute hydrochloric acid,evaporating to dryness and recrystallising the residue from aqueousethanol.

(Found: C, 31.1; H, 5.4; N, 21.45; S, 9.7; Cl, 21.6; C₁₀ N₁₇ Cl₂ N₅ OSrequires: C, 36.8; H, 5.25; N, 21.5; S, 9.8; Cl, 21.7).

EXAMPLE 8 2-[2-(4-Methyl)-5-imidazolylmethylthio)ethylamino]-4(1H)-quinazolinone

Reaction of an intimate mixture of4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.6 g.) with2-methylthio-4(1H)-quinazolinone (1.9 g.) at 120° for 41/2 hours gavethe crude base (2.7 g.) which was acidified with hydrochloric acid asdescribed in Example 1, to give, on recrystallisation fromethanol/ether,2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4(1H)-quinazolinonedihydrochloride, m.p. 249°-252°.

(Found: C, 45.8; H, 4.9; N, 17.8; S, 8.1 C₁₅ H₁₄ Cl ₂ N₅ OS requires: C,46.4; H, 4.9; N, 18.0; S, 8.3).

EXAMPLE 92-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-n-propyl-4-pyrimidone

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (5 g.)with 6-n-propyl-2-methylthio-4-pyrimidone (5 g.) by the method describedin Example 1 gave a hygroscopic dihydrochloride of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-6-n-propyl-4-pyrimidone,m.p. 125°-130° (crystallised from butanol/ether).

(Found: C, 44.3; H, 6.2; N, 18.3; S, 8.2; Cl, 18.7. C₁₄ H₂₃ Cl₂ N₅ OSrequires: C, 44.2; H, 6.1; N, 18.4; S, 8.4; Cl, 18.6).

EXAMPLE 102-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidonedihydrochloride

Reaction of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (2.0 g.)with 5-ethyl-6-methyl-2-methylthio-4-pyrimidone (1.46 g.) by the methoddescribed in Example 1 gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidonedihydrochloride m.p. 203°-7° (crystallised from isobutanol)

(Found: C, 43.6; H, 6.1; N, 17.9; S, 8.0; Cl, 18.5. C₁₄ H₂₃ Cl₂ N₅ O₆requires: C, 44.2; H, 6.1; N, 18.5; S, 8.4; Cl, 18.6).

EXAMPLE 112-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-methyl-2-imidazolin-4-one

A solution of 5-methyl-2-thiohydantoin (15 g.) and methyl iodide (16.3g.) in dry ethanol (130 ml.) was heated under reflux for 11/2 hours, andthen allowed to stand at 0° overnight. The crystalline product wasfiltered and washed with ether to give2-methylthio-5-methyl-2-imidazolin-4-one hydroiodide (17.8 g.), m.p.170°-173°.

A solution of this hydroiodide (2.7 g.), 4(5)-aminoethyl)thiomethyl-5(4)-methylimidazole (2.5 g.) and triethylamine (1 g.) in dryethanol (20 ml.) was left to stand at room temperature for 10 days. Theresulting crude product (1.6 g., m.p. 218°) was dissolved inhydrochloric acid and the solution basified with saturated aqueouspotassium carbonate solution to give hydrated2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-methylimidazolin-4-one,m.p. 216°-220°.

(Found: C, 48.5; H, 6.4; N, 25.4; S, 11.9. C₁₁ H₁₇ N₅ OS 1/3 H₂ O.requires: C, 48.3; H, 6.5; N, 25.6; S, 11.7).

EXAMPLE 125,5-Dimethyl-2-[2-(4-methyl-5-imidazolylmethylthio)-ethylamino]-2-imidazolin-4-one

5,5-Dimethyl-2-thiohydantoin (14.4 g.) was converted to2-methylthio5,5-dimethyl-2-imidazolin-4-one hydroiodide (17.4 g., m.p.187°-189°) according to the method described in Example 11. A solutionof this hydroiodide (5.7 g.) and 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (6.85 g.) in dry ethanol(45 ml.) was left to stand at room temperature for 4 days. The reactionmixture was evaporated to dryness and the residue recrystallised fromwater to give5,5-dimethyl-2-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]-2-imidazolin-4-one(3.1 g.) m.p. 232°-236°. Further recrystallisation from water gave ananalytical sample, m.p. 235°-7°.

(Found: C, 50.9; H, 6.9; N, 24.8; S, 11.4; C₁₂ H₁₉ N₅ OS. requires: C,51.2; H, 6.8; N, 24.9; S, 11.4).

EXAMPLE 135-Benzyl-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one

5-Benzyl-2-thiohydantoin was converted to 2-methylthio-5-benzyl-2-imidazolin-4-one hydroiodide (m.p. 192°-194°) according to themethod described in Example 11.

A solution of this hydroiodide (2.5 g.),4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (1.9 g.) andtriethylamine (0.74 g.) in dry ethanol (15 ml.) was left to stand atroom temperature for 4 days. The reaction mixture was evaporated todryness, the residue dissolved in isopropanol (25 ml.) and the resultingsolution poured into ether (200 ml.) to give5-benzyl-2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-2-imidazolin-4-one(1.23 g.) m.p. 104°-7°.

EXAMPLE 14 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]pyrimid-4-thione dihydrochloride

A mixture of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone (5 g.)and phosphorus pentasulphide (4 g.) in pyridine (150 ml.) was heatedunder reflux, with stirring, for 2 hours. The reaction mixture wasevaporated to dryness, boiled with water for 30 minutes and againevaporated to dryness. The residue was dissolved in dilute ammoniumhydroxide, the solution washed with chloroform and the aqueous layerevaporated to dryness. Concentrated hydrochloric acid was added to theresidue to give a pale yellow solid, which was dissolved in warm water,filtered, and the filtrate acidified with concentrated hydrochloric acidto give2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]pyrimid-4-thionedihydrochloride, m.p. 245°-247°.

(Found: C, 37.0; H, 4.9; N, 19.55; S, 17.7; C₁₁ H₁₇ Cl₂ N₅ S₂. requires:C, 37.3; H, 4.8; N, 19.8; S, 18.1.).

EXAMPLE 15 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-6-one

A mixture of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (20 g.)and 2-brono-6-ethoxy-pyridine (11.9 g.) was heated with stirring at 160°for 4 hours. After cooling, the reaction mixture was dissolved in 20%aqueous hydrobromic acid and the solution extracted with ether torecover unchanged 2-bromo-6-ethoxypyridine. The aqueous layer wasbasified with potassium carbonate, extracted with chloroform and thecombined extract washed with water and dried (MgSo₄). After removal ofthe chloroform the residue was chromatographed on silica gel. elutingwith first ethyl acetate to remove impurities and then ethylacetate/methanol/chloroform (4:1:2) to elute the required product.Evaporation of the eluate gave2-ethoxy-6-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]pyridine as anoil, which on treatment with a solution of picric acid in ethanol gavethe dipicrate, m.p. 172°.

A solution of this ethoxypyridine (3.4 g. of base) in 5N hydrochloricacid (100 ml) was heated under reflux for 21/2 hours. The reactionmixture was evaporated to dryness, the residue dissolved in a minimumamount of water, the solution basified with aqueous potassium carbonate,washed once with chloroform, and allowed to stand at 0° overnight.Crystals of2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-6-one werecollected and recrystallised from water to give the pure product, m.p.85°.

(Found: C, 54.25; H, 6.0; N, 20.9; S, 11.9. C₁₂ H₁₆ N₄ OS. requires: C,54.5; H, 6.1; N, 21.2; S, 12.1).

EXAMPLE 162-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one

A mixture of 4(5)-(2-aminoethyl)thiomethyl-5(4)-methylimidazole (7.6 g.)and 2-bromo-4-pyridone (3.8 g.) was heated with stirring at 160° for 3hours. After cooling, the reaction mixture was chromatographed on silicagel, eluting with first ethyl acetate isopropanol (5:1) to removeunreacted 2-bromo-4-pyridone and then isopropanol/ethanol (5:1) toremove the product. After evaporation of the combined eluates theresidue was purified further by ion-exchange chromatography using IRA400 (OH form) resin and eluting first with water to remove unchangedamine and then IN hydrochloric acid to remove the product. Evaporationof the acid fractions and recrystallisation of the residue fromisopropanol/ethyl acetate gave2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-(1H)-pyrid-4-one, m.p.208°-210°.

EXAMPLE 173-[2-((4-Methyl-5-imidazolylmethylthio)ethyl)amino]-1,2,4-benzothiadiazine-1,1,-dioxide

A mixture of 3-methylmercapto-1,2,4-benzothiadiazine-1,1-dioxide (5.58g.) and 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.20 g.) washeated at 140°-150° for 2 hours and then cooled. Following dissolutionin ethanol, and cooling the crude product was obtained as a solid (5.67g.) which was recrystallised from water and then methanol to give3-[2-((4-methyl-5-imidazolylmethylthio)ethyl)amino]-1,2,4-benzothiadiazine-1,1-dioxide(4.30 g.), m.p. 194.5°-196°.

(Found: C, 48.0; H, 5.0; N, 19.8; S, 18.2. C₁₄ H₁₇ N₅ O₂ S₂. requires:C, 47.8; H, 4.9; N, 19.9; S, 18.3).

EXAMPLE 183-[2-((4-Methyl-5-imidazolyl)methylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide

A mixture of 4-methyl-5-((2-aminoethyl)thiomethyl)imidazole (4.0 g.) and3-methylthio-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide (4.2 g.) washeated in an oil bath at 140° for 4 hours. The product waschromatographed on a column of silica gel with ethyl acetate-ethanol(3:2) as eluant and finally recrystallised from ethanol-ether to give3-[2-((4-methyl-5-imidazolyl)methylthio)ethylamino]-5,6-dihydro-1,2,4-thiadiazine-1,1-dioxide(2.2 g.) m.p. 146°-147°.

(Found: C, 39.6; H, 6.0; N, 22.9. C₁₀ N₁₇ N₅ O₂ S₂. requires: C, 39.6;H, 5.7; N, 23.1).

EXAMPLE 194-[2-((4-Methyl-5-imidazolylmethylthio)ethylamino]thiazoline-2-one

A solution of 4-methyl-5-[(2-aminoethyl)thiomethyl]imidazole (1.71 g.)and thiazolidine-2-one-4-thione (1.33 g.) in methanol (30 ml.) washeated under reflux for one hour. Concentration, followed by successiverecrystallisation of the residue from methanol, ethanol and aqueousethanol afforded4-[2-(4-methyl-5-imidazolyl)methylthio)ethylamino]thiazoline- 2-one (1.0g.) m.p. 195°-197°.

(Found: C, 44.2; H, 5.1; N, 20.5; S, 23.6.C₁₀ H₁₄ N₄ OS₂. requires: C,44.4; H, 5.2; N, 20.7; S, 23.7).

EXAMPLE 203-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-6-methyl-1,2,4-triazin-2H-5-one

An intimate mixture of 3-methylthio-6-methyl-1,2,4-triazine-2H-5-one(7.64 gms) and 5-(2-aminoethyl)thiomethyl-4-methylimidazole (8.75 gms)was heated slowly to 160° C and maintained at this temperature for onehour. After cooling the resulting solid was dissolved in 2N.HCl (100ml), filtered and the filtrate basified with aqueous K₂ CO₃ solution.The resulting precipitate was collected, washed with water, dried andextracted in a Soxhlet extractor with methanol for 16 hours. Themethanol solution was cooled giving yellow-buff crystals.Recrystallisation from dimethylsulphoxide gave3-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-o-methyl-1,2,4-triazin-2H-5-one. (7.8 gms.), m.p. 264°-266° C (Dec).

(Found: C, 46.8; H, 5.7; N, 29.9; S, 12.0; C₁₁ H₁₆ N₆ OS. requires: C,47.1; H, 5.7; N, 30.0; S, 11.44).

EXAMPLE 213-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-1,2,4-triazin-2H-5-one

An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methyl imidazole(8.6 gms) and 3-methylthio triazin-2H-5-one (6.68 gms) was slowly heatedto 120° C and kept at this temperature for 4 hours. After cooling theresulting solid was recrystallised twice from n-propanol and twice fromwater to give3-[2-(5-methyl-4-imidazolylmethylthio)ethylamino]-1,2,4-triazin-2H-5-one,m.p. 238°-238.5° C.

(Found: C, 45.1; H, 5.55; N, 31.5; S, 11.9; C₁₀ H₁₄ N₆ OS. requires: C,45.1; H, 5.3; N, 31.6; S, 12.0).

EXAMPLE 222-[2-(-Methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone

5-Benzyl-o-methylthiouracil (6.0 gms) and sodium hydroxide (1.06 gms)were dissolved in water (30 mls). The solution was cooled and ethanol(60 mls) and methyl iodide (3.67 gms) added with stirring. The mixturewas heated at 60° C for 1/2 hour, cooled and the resulting solidcollected and water-washed. A second crop of solid was obtained byacidification of the filtrate to pH=4 with acetic acid.Recrystallisation from ethanol produced 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (5.53 gms) m.p. = 220°-221.5° C.

An intimate mixture of 5-(2-aminoethyl)thiomethyl-4-methylimidazole(1.28 gms) and 5-benzyl-6-methyl-2-methylthio-4-pyrimidone (1.84 gms)was heated at 150°-160° C (oil-bath temperature) for 41/2 hours. Themixture was cooled, washed with water and recrystallised fromisopropanol to give2-[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone(1.82 gms) m.p. = 140°-141.5° C.

(Found: C, 61.7; H, 6.6; N, 18.5; S, 8.20; C₁₉ H₂₃ N₅ OS. requires: C,61.8; H, 6.3; N, 18.95; S, 8.68).

EXAMPLE 23 2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone

2-Chloro-4-ethoxyquinoline (3.72 gms) and5-(2-aminoethyl)thiomethyl-4-methylimidazole (3.1 g.) were heatedtogether at 150°-160° C (oil-bath temperature) for 3 hours. The residue,on cooling, was washed with water and dried. Purification was effectedby column chromatography (silica gel column, ethyl acetate-5% methanoleluant) and crystallisation from acetone to give2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-ethoxyquinoline(1.86 gms) m.p. 152.5°-153.5° C.

(Found: C, 63.2; H, 6.5; N, 16.1; S, 9.1. C₁₈ H₂₂ N₄ OS. requires: C,63.1; H, 6.5; N, 16.4; S, 9.4).

2-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]4-ethoxyquinoline (1.69gms) and concentrated HCl (30 mls) were refluxed together for 17 hours.The solution was evaporated to dryness, the residue dissolved in waterand basified with potassium carbonate. The precipitated oil wasseparated by decantation, washed with water and crystallised fromisopropanol-water to give2[-2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-quinolone. m.p.121°-124° C.

(Found; C, 60.1; H, 5.7; N, 17.1; S, 9.9; C₁₆ H₁₈ N₄ OS. requires; C,61.1; H, 5.8; N, 17.8; S, 10.2).

EXAMPLE 24 4-[4-(4-Imidazolyl)butylamino]-2-thiopyrimidone

Reaction of 4(5)-(4-aminobutyl)imidazole (2.8 g.) with2,4-dimercaptopyrimide (1.44 g.) by the method described in Example 5gave 4-[4-(4-imidazolyl)butylamino]-2-thiopyrimidone, m.p. 209°-211° (exn-propanol).

(Found: C, 51.4; H, 6.3; N, 27.0; S, 13.0 C₁₁ H₁₅ N₅ S. 0.4 H₂ O.requires: C, 51.6; H, 6.3; N, 27.35; S. 12.5).

EXAMPLE 25

Reaction of 2-methylthio-4-pyrimidone by the procedure of Example 1 withthe following compounds:

4-[(2-aminoethyl)thiomethyl]imidazole

4-(2-aminoethyl)thiomethyl-5-bromoimidazole

4-[(3-aminopropyl)thiomethyl]imidazole

2-(2-aminoethyl)thiomethyl-3-bromopyridine

2-(2-aminoethyl)thiomethyl-3-hydroxypyridine

2-(2-aminoethyl)thiomethyl-3-methylpyridine

2-(2-aminoethyl)thiomethyl-3-aminopyridine

2-[(2-aminoethyl)thiomethyl]thiazole

2-(4-aminobutyl)thiazole

3-[(2-aminoethyl)thiomethyl]isothiazole

3-(2-aminoethyl)thiomethyl-4-bromoisothiazole

2-amino-5-(2-aminoethyl)thiomethyl-1,3,4thiadiazole

4-(5-aminopentyl)imidazole

yields the following products:

2-[2-(4-imidazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(4bromo-5-imidazolylmethylthio)ethylamino]-4-pyrimidone

2-[3-(4-imidazolylmethylthio)propylamino]-4-pyrimidone

2-[2-(3-bromo-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-hydroxy-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-methyl-2 -pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(3-amino-2-pyridylmethylthio)ethylamino]-4-pyrimidone

2-[2-(2-thiazolylmethylthio)ethylamino]-4-pyrimidone

2-[4-(2-thiazolyl)butylamino]-4-pyrimidone

2-[2-(3-isothiazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(4-bromo-3-isothiazolylmethylthio)ethylamino]-4-pyrimidone

2-[2-(2-amino-5-(1,3,4-thiadiazolyl)methylthio)ethylamino]-4-pyrimidone

2-[5-(4-imidazolyl)pentylamino]-4-pyrimidone

EXAMPLE 262-[2-(4-Methyl-5-imidazolylmethylthio)ethylamino]-5-phenyl-6-methyl-4-pyrimidone

When 5-phenyl-6-methylthiouracil is used as the starting material in theprocedures of Example 22 the title compound, m.p. 215.5°-217.5° C, isproduced.

27

                  Example 27                                                      ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        2-[2-(4-methyl-5-imidazolylmethylthio)-                                       ethylamino]-4-pyrimidone 150 mg                                               Sucrose                  75 mg                                                Starch                   25 mg                                                Talc                     5 mg                                                 Stearic Acid             2 mg                                                 ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule.

EXAMPLE 28

                  EXAMPLE 28                                                      ______________________________________                                        Ingredients              Amounts                                              ______________________________________                                        2-[2-(4-Methyl-5-imidazolylmethylthio)-                                       ethylamino]-5-benzyl-6-methyl-4-pyrimidone                                                             200 mg                                               Lactose                  100 mg                                               ______________________________________                                    

The ingredients are screened, mixed and filled into a hard gelatincapsule

What we claim is:
 1. A pharmaceutical composition to inhibit H-2histamine receptors, said H-2 histamine receptors being those histaminereceptors which are not inhibited by mepyramine but are inhibited byburimamide, comprising a pharmaceutical carrier and in an effectiveamount to inhibit said receptors a heterocyclic compound of the formula:##STR4## wherein A taken together with the nitrogen and carbon atomsshown forms a pyrimidine ring, said ring having a keto or thione groupand optionally substituted by one or two lower alkyl, phenyl or benzylgroups; R is a grouping of the formula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is an imidazole ring, said ring being optionally substitutedby lower alkyl, amino, hydroxy or halogen; Z is sulphur or a methylenegroup and n is 2 or 3 or a pharmaceutically acceptable acid additionsalt thereof.
 2. A method of inhibiting H-2 histamine receptors, saidH-2 histamine receptors being those histamine receptors which are notinhibited by mepyramine but are inhibited by burimamide, which comprisesadministering to an animal in need of inhibition of said receptors in aneffective amount to inhibit said receptors a heterocyclic compound ofthe formula: ##STR5##wherein A taken together with the nitrogen andcarbon atoms shown forms a pyrimidine ring, said ring having a keto orthione group and optionally substituted by one or two lower alkyl,phenyl or benzyl groups; R is a grouping of the formula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is an imidazole ring, said ring being optionally substitutedby lower alkyl, amino, hydroxy or halogen; Z is sulphur or a methylenegroup and n is 2 or 3 or a pharmaceutically acceptable acid additionsalt thereof.
 3. A pharmaceutical composition of claim 1 in which theheterocyclic compound is of the formula: ##STR6##wherein R has the samesignificance in claim 1; X is oxygen or sulphur and Y₁ and Y₂, which maybe the same or different, are hydrogen, lower alkyl, phenyl or benzyl.4. A pharmaceutical composition of claim 1 in which the heterocycliccompound is2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone.
 5. Apharmaceutical composition of claim 1 in which the heterocyclic compoundis2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidone.6. A pharmaceutical composition of claim 1 in which the heterocycliccompound is2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone.7. A pharmaceutical composition of claim 1 in which the heterocycliccompound is present in an amount of from about 50 mg. to about 250 mg.8. A method of claim 2 in which the heterocyclic compound is of theformula: ##STR7##wherein R has the same significance as in claim 2; X isoxygen or sulphur and Y₁ and Y₂, which may be the same or different, arehydrogen, lower alkyl, phenyl or benzyl.
 9. A method of claim 2 in whichthe heterocyclic compound is2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-4-pyrimidone.
 10. Amethod of claim 2 in which the heterocyclic compound is2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-ethyl-6-methyl-4-pyrimidone.11. A method of claim 2 in which the heterocyclic compound is2-[2-(4-methyl-5-imidazolylmethylthio)ethylamino]-5-benzyl-6-methyl-4-pyrimidone.12. A method of claim 2 in which the heterocyclic compound isadministered in a daily dosage of from about 150 mg. to about 750 mg.13. A method of inhibiting gastric acid secretion which comprisesadministering internally to an animal in need of inhibition of gastricacid secretion in an effective amount to inhibit gastric acid secretiona heterocyclic compound of the formula: ##STR8##wherein A taken togetherwith the nitrogen and carbon atoms shown forms a pyrimidine ring, saidring having a keto or thione group and optionally substituted by one ortwo lower alkyl, phenyl or benzyl groups; R is a grouping of theformula:

    Het--CH.sub.2 Z(CH.sub.2).sub.n --

wherein Het is an imidazole ring, said ring being optionally substitutedby lower alkyl, amino, hydroxy or halogen; Z is sulphur or a methylenegroup and n is 2 or 3 or a pharmaceutically acceptable acid additionsalt thereof.